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P-gp inducers as protectors against chemotherapy-induced side effects, such as peripheral neuropathy (CIPN) and hair loss

a technology of inducers and inducers, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, dermatological disorders, etc., can solve the problems of paclitaxel provoking multiple side effects in patients, affecting the effect of paclitaxel treatment, and affecting so as to prevent the effect of cipn and hair loss

Pending Publication Date: 2022-10-06
SYDDANSK UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about the use of a drug that induces P-gp and / or MRP1 to prevent side effects of chemicals that are transported out of cells by these proteins. By applying the drug to the hands, feet, scalp, or other areas before chemotherapy treatment, it can prevent skimming or alopecia. This approach involves using a drug that helps regulate the transport of chemicals by P-gp and MRP1 to protect against their side effects.

Problems solved by technology

Clinical signs of CIPN include sensory loss, paresthesia, dysesthesia, numbness and tingling and often leads to neuropathic pain.
While effective, paclitaxel provokes multiple side effects in patients.
A common and potentially serious adverse reaction to treatment with paclitaxel is peripheral neuropathy, which occurs in up to 50% of all patients.
CIPN can be very serious, but even mild to moderate symptoms may persist for several years after treatment cessation, significantly impairing quality of life.
While less impactful on treatment success, hair loss presents a substantial psychological issue for cancer patients and survivors.
Hair loss is also costly for the healthcare providers as wigs are needed for the patients.

Method used

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  • P-gp inducers as protectors against chemotherapy-induced side effects, such as peripheral neuropathy (CIPN) and hair loss
  • P-gp inducers as protectors against chemotherapy-induced side effects, such as peripheral neuropathy (CIPN) and hair loss
  • P-gp inducers as protectors against chemotherapy-induced side effects, such as peripheral neuropathy (CIPN) and hair loss

Examples

Experimental program
Comparison scheme
Effect test

example 1

l Affects Neuronal Morphology

[0170]Aim of Study

[0171]To evaluate how Paclitaxel affects neuronal morphology.

[0172]Materials and Methods

[0173]Cell Culture

[0174]SH-SY5Y cells (94030304, Sigma-Aldrich) were kept in DMEM / F:12 (11320074, ThermoFisher) with 15% heat-inactivated fetal bovine serum (hiFBS, F9665 Sigma-Aldrich), 1% penicillin / streptomycin (p / s) and 2 mM glutamine. Cells were split 1:10-1:20 using 0.05% trypsin-EDTA (10779413, Fisher Scientific) at 70-80% confluence. At high passage number, the epithelial cell type takes over the culture and causes drastically reduced efficiency of the differentiation. Thus, cells were only used below passage 15.

[0175]Reagents and Antibodies

[0176]Paclitaxel (T7402, Sigma-Aldrich) was diluted serially in DMSO (D2650, Sigma-Aldrich) and these stock solutions diluted 1:500 to ensure 0.2% DMSO in all samples. These concentrations were selected based on the clinical pharmacokinetic profile of paclitaxel. Valspodar (SML0572, Sigma-Aldrich) were use...

example 2

ular Concentrations of Paclitaxel

[0194]Aim of Study

[0195]To confirm that the increased harmful effect of paclitaxel on neuronal morphology under conditions of P-gp inhibition is related to increased exposure, the intracellular concentrations of paclitaxel were quantified.

[0196]Materials and Methods

[0197]Cells were treated with paclitaxel with and without concomitant P-gp inhibition by valspodar and intracellular levels were measured 1 hour after treatment.

[0198]For further details, see also materials and methods section in example 1.

[0199]Results

[0200]Inhibition of P-gp caused a >3-fold increase in intracellular accumulation of paclitaxel at 10 μM (p<0.001, FIG. 3).

[0201]Conclusion

[0202]P-gp inhibition causes increased accumulation of paclitaxel in SH-SY5Y-derived neurons. Again, these data suggest that stimulating P-gp would have the opposite effect and thus also that CIPN could be prevented by applying such P-gp inducers to the skin.

example 3

bitors and Paclitaxel-Induced Peripheral Neuropathy in Patients

[0203]Aim of Study

[0204]To assess if concomitant ingestion of P-gp inhibitors causes increased risk of peripheral neuropathy among patients treated with paclitaxel.

[0205]Materials and Methods

[0206]P-Gp Inhibitors and Paclitaxel-Induced Peripheral Neuropathy in Patients

[0207]To assess if P-gp inhibition leads to increased risk of peripheral neuropathy we used a previously described database of 503 paclitaxel treated patients with breast or ovarian cancer (Sanchez-Barroso L et al. The Oncologist. 2018 Nov. 23). Briefly, dose-modifications due to peripheral neuropathy were collected from medical records and multivariate logistic regression was performed to assess if users of P-gp inhibitors had a higher risk of dose modifications due to neuropathy. P-gp inhibitors were selected based on two literature reviews (see comments under table 1). From these reviews, we identified drugs listed as P-gp inhibitors (drugs classified as...

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Abstract

The present invention relates to compositions comprising a P-gp inducer, for topical use in preventing one or more side effects of chemotherapeutics, which chemotherapeutics are transported out of cells by P-gp. Especially chemotherapy-induced peripheral neuropathy (CIPN) is a relevant side effect to treat / avoid, since CIPN may be a dose limiting side effect of chemotherapy. The invention also relates to kits and to cancer treatment of a subgroup of patients, which subgroup has been topically pretreated with a P-gp inducer.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The present invention relates to compositions comprising P-gp inducers and / or MRP1 inducers for use in protection against side effects of chemotherapy, such as chemotherapy-induced peripheral neuropathy (CIPN), wherein the inducer is to be topically applied. The invention also relates to improved treatment of a subgroup of cancers patients, who have been topically pretreated with a P-gp inducer and / or MRP1 inducer.BACKGROUND OF THE INVENTION[0002]A known side effect of many cytotoxic anticancer drugs is the development of Chemotherapy-induced peripheral neuropathy (CIPN). Clinical signs of CIPN include sensory loss, paresthesia, dysesthesia, numbness and tingling and often leads to neuropathic pain. Another known side effect is hair loss (alopecia).[0003]Paclitaxel is a cytotoxic anticancer drug used in the treatment of solid organ tumours such as breast cancer and ovarian cancer. Paclitaxel is also used in adjuvant and neoadjuvant chemotherapy....

Claims

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Application Information

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IPC IPC(8): A61K31/337A61K31/475A61P17/14A61P25/02A61P35/00A61K31/55A61K31/57A61K9/00
CPCA61K31/337A61K31/475A61P17/14A61P25/02A61P35/00A61K31/55A61K31/57A61K9/0014A61K45/06A61P43/00A61K31/496A61K31/573A61K2300/00
Inventor STAGE, TORE BJERREGAARD
Owner SYDDANSK UNIV
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